Symmetrical choline-derived dications display strong anti-kinetoplastid activity

Ibrahim, Hasan M. S.; Al-Salabi, Mohammed I.; Sabbagh, Nasser El; Quashie, Neils B; Alkhaldi, Abdulsalam A. M.; Escale, R.; Smith, Terry; Vial, Henri; Koning, Harry P. de

doi:10.1093/jac/dkq401

Cited by 38 publications

(79 citation statements)

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“…It is also not dependent on entry through the P2 and HAPT transporters. These results, similar to a series of dicationic choline-derived compounds, 9 indicate that diffusion is the most probable mechanism of uptake into trypanosomes, although the presence of an unknown transporter for lipophilic cations cannot be excluded. However, it is likely that the lipophilic ammonium and phosphonium compounds would have to pass both the plasma membrane and the mitochondrial membrane, as such compounds are generally believed to accumulate, and act, in the mitochondria (De Koning, manuscript in preparation).…”

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confidence: 71%

“…6,7 These compounds display a good selectivity index relative to human cell lines, are not cross-resistant with existing trypanocides, and require only a short exposure time for trypanocidal activity. 6 Like other dicationic trypanocides, 8,9 the bisphosphonium salts are expected to accumulate in the mitochondria. Indeed, a mitochondrial target for these compounds was demonstrated in Leishmania.…”

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confidence: 99%

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SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts

Dardonville

Alkhaldi

Koning

2014

ACS Med. Chem. Lett.

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ABSTRACT:In previous studies, we have shown that phosphonium salt diphenyl derivatives are attractive antitrypanosomal hit compounds with EC 50 values against Trypanosoma brucei in the nanomolar range. To evaluate the role of the cationic center on the trypanocidal activity and extend the structure−activity relationship (SAR) of this series, trialkylammonium, pyridinium, and quinolinium salt analogues were synthesized and evaluated in vitro against T. b. brucei. Similar SARs were observed with ammonium and phosphonium salts showing that charge dispersion and lipophilic groups around the cationic center are crucial to obtain submicromolar activities. The new compounds were equally effective against wild type (T. b. brucei s427) and resistant strains (TbAT1-KO and TbB48) of trypanosomes indicating that the P2 and high affinity pentamidine transporters (HAPT) are not essential to their trypanocidal action. Similarly to phosphonium salt derivatives, diffusion seems to be the main route of entry into trypanosomes. KEYWORDS: Trypanosoma brucei, ammonium salt, quinolinium salt, pyridinium salt, P2-transporter, high affinity pentamidine transporter (HAPT) P arasitic protozoa of the genus Trypanosoma cause human and animal trypanosomiases in Africa. Two subspecies of T. brucei (T. b. gambiense and T. b. rhodesiense) are pathogenic to man and cause human African trypanosomiasis (HAT) in sub-Saharan Africa. In contrast, T. b. brucei, T. congolense, and T. vivax cause veterinary diseases in domestic and wild animals. 1,2 African trypanosomiasis is one of the most neglected tropical diseases as shown by the lack of safe drugs to treat both (early and late) stages of the illness. These drugs, which have been used for decades, are subject to treatment failure (drug resistance) and have severe drawbacks such as unacceptable toxicity and parenteral administration. 3 Cationic drugs are an important class of trypanocides used for the treatment of human and veterinary trypanosomiasis (e.g., pentamidine, diminazene, homidium, and isomethamidium). 4,5 In previous studies we have shown that a new class of cationic compounds, mono-and bisphosphonium salt derivatives with a diphenyl scaffold, have submicromolar activities against T. brucei and Leishmania parasites. 6,7 These compounds display a good selectivity index relative to human cell lines, are not cross-resistant with existing trypanocides, and require only a short exposure time for trypanocidal activity. 6 Like other dicationic trypanocides, 8,9 the bisphosphonium salts are expected to accumulate in the mitochondria. Indeed, a mitochondrial target for these compounds was demonstrated in Leishmania. 7 Structure−activity relationship (SAR) studies revealed that bulky substituents on the phosphorus atoms are required to achieve submicromolar EC 50 values within this series. In the present work, we wanted to learn whether the nature of the cationic center was important for the observed trypanocidal activity of these hit compounds. Thus, new cationic analogues of the hits with a nitr...

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confidence: 71%

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confidence: 99%

SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts

Dardonville

Alkhaldi

Koning

2014

ACS Med. Chem. Lett.

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“…The latter would most likely involve changes in mitochondrial function, because this organelle is believed to be the main target of diamidines in kinetoplastids (Basselin et al, 2002;Lanteri et al, 2008). Other dications, including bisphosphonium salts and choline-derived compounds similarly target mitochondria in Leishmania and Trypanosoma species (Ibrahim et al, 2011;Luque-Ortega et al, 2010). The possibility of specific mitochondrial changes being involved in diamidine resistance in African trypanosomes is the subject of ongoing investigations in our laboratories.…”

Section: Discussionmentioning

confidence: 99%

The Diamidine Diminazene Aceturate Is a Substrate for the High-Affinity Pentamidine Transporter: Implications for the Development of High Resistance Levels in Trypanosomes

Teka

Kazibwe²,

El-Sabbagh³

et al. 2011

Mol Pharmacol

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African trypanosomiasis is a disease of humans and livestock in many areas south of the Sahara. Resistance to the few existing drugs is a major impediment to the control of these diseases, and we investigated how resistance to the main veterinary drug diminazene aceturate correlates with changes in drug transport in resistant strains. The strain tbat1(Ϫ/Ϫ), lacking the TbAT1/P2 aminopurine transporter implicated previously in diminazene transport, was adapted to higher levels of diminazene resistance. The resulting cell line was designated ABR and was highly cross-resistant to other diamidines and moderately resistant to cymelarsan. Procyclic trypanosomes were shown to be a convenient model to study diamidine uptake in Trypanosoma brucei brucei given the lack of TbAT1/P2 and a 10-fold higher activity of the high-affinity pentamidine transporter (HAPT1). Diminazene could be transported by HAPT1 in procyclic trypanosomes. This drug transport activity was lacking in the ABR line, as reported previously for the pentamidineadapted line B48. The K m for diminazene transport in bloodstream tbat1(Ϫ/Ϫ) trypanosomes was consistent with uptake by HAPT1. Diminazene transport in ABR and B48 cells was reduced compared with tbat1(Ϫ/Ϫ), but their resistance phenotype was different: B48 displayed higher levels of resistance to pentamidine and the melaminophenyl arsenicals, whereas ABR displayed higher resistance to diminazene. These results establish a loss of HAPT1 function as a contributing factor to diminazene resistance but equally demonstrate for the first time that adaptations other than those determining the initial rates of drug uptake contribute to diamidine and arsenical resistance in African trypanosomes.

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“…The intracellular calcium level was measured using the Screen Quest Fluo-8 Calcium Kit produced by ABD Bioquest (Sunnyvale, CA) (Ibrahim et al, 2011). Briefly, cultures of bloodstream-form T. b. brucei Lister 427 were harvested and washed by centrifugation at 2500g for 10 minutes at 4°C, resuspended to a final density of 4 Â 10 6 cells/ml in the Fluo-8 dye-loading solution, and further incubated at 37°C for 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

“…As this fluorophore does not cross the intact T. b. brucei plasma membrane, monitoring its fluorescence (l exc 5 544 nm; l em 5 620 nm) generates an output proportionate to the number of cells with compromised cell membrane integrity (Gould et al, 2008). The assay was performed in 96-well plates with doubling dilutions of the test compounds (as well as no-drug controls), 9 mM propidium iodide, and 5 Â 10 6 cells/ml in a FLUOstar Optima fluorometer fitted with environmental controls (37°C, 5% CO 2 ) (Ibrahim et al, 2011).…”

Section: Methodsmentioning

confidence: 99%

Potent Trypanocidal Curcumin Analogs Bearing a Monoenone Linker Motif Act on Trypanosoma brucei by Forming an Adduct with Trypanothione

et al. 2014

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We have previously reported that curcumin analogs with a C 7 linker bearing a C 4 -C 5 olefinic linker with a single keto group at C3 (enone linker) display midnanomolar activity against the bloodstream form of Trypanosoma brucei. However, no clear indication of their mechanism of action or superior antiparasitic activity relative to analogs with the original di-ketone curcumin linker was apparent. To further investigate their utility as antiparasitic agents, we compare the cellular effects of curcumin and the enone linker lead compound 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (AS-HK014) here. An AS-HK014-resitant line, trypanosomes adapted to AS-HK014 (TA014), was developed by in vitro exposure to the drug. Metabolomic analysis revealed that exposure to AS-HK014, but not curcumin, rapidly depleted glutathione and trypanothione in the wild-type line, although almost all other metabolites were unchanged relative to control. In TA014 cells, thiol levels were similar to untreated wild-type cells and not significantly depleted by AS-HK014. Adducts of AS-HK014 with both glutathione and trypanothione were identified in AS-HK014-exposed wild-type cells and reproduced by chemical reaction. However, adduct accumulation in sensitive cells was much lower than in resistant cells. TA014 cells did not exhibit any changes in sequence or protein levels of glutathione synthetase and g-glutamylcysteine synthetase relative to wild-type cells. We conclude that monoenone curcuminoids have a different mode of action than curcumin, rapidly and specifically depleting thiol levels in trypanosomes by forming an adduct. This adduct may ultimately be responsible for the highly potent trypanocidal and antiparasitic activity of the monoenone curcuminoids.

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Symmetrical choline-derived dications display strong anti-kinetoplastid activity

Cited by 38 publications

References 65 publications

SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts

SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts

The Diamidine Diminazene Aceturate Is a Substrate for the High-Affinity Pentamidine Transporter: Implications for the Development of High Resistance Levels in Trypanosomes

Potent Trypanocidal Curcumin Analogs Bearing a Monoenone Linker Motif Act on Trypanosoma brucei by Forming an Adduct with Trypanothione

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